Current therapies for multiple sclerosis (MS) target the immune system in an effort to control its destructive actions in the central nervous system during autoimmune disease. Unfortunately, the approved therapies usually act globally to affect many cells of the immune system and not just the autoreactive cells causing disease. To improve upon the current therapies, many groups, including our own, are attempting to selectively target the myelin specific T cells supporting and propagating the anti-self response. Our efforts have focused on mutating the myelin peptide antigen to make variants with low affinity for the MHC molecule while retaining their ability to interact at biological levels with T cells. These MHC variant peptides (abbreviated here as MVPs) induce T cell anergy, prevent the initiation of autoimmune disease, and reduce the severity of ongoing EAE in polyclonal populations of T cells in two EAE models. Thus, MHC variant peptides retain antigen specific effects by targeting myelin-reactive T cells without the broad immunosuppressive consequences or side effects of the current clinical therapies used in MS. The phenotype induced using MHC variant peptides manifests itself as T cell anergy with an observed decrease in T cell proliferation, IL-2 production, and IL-2 response. In addition, the MVP effects do not promote a shift in T helper polarization (measured as conserved IFN gammaproduction). To expand on our initial promising findings and to assess the mechanism of MVP action, we have generated exciting preliminary data that suggests the tyrosine phosphatase SHP-1 is an important point of control for the intensity of autoimmune disease. We hypothesize that methods, which increase SHP-1 activity in T cells can lead to the induction of anergy in those myelin specific cells. These anergic T cells in turn can moderate other myelin reactive T cells, thus providing a potential treatment for autoimmune disease. Two specific aims are designed to test this hypothesis. Aim 1: To define SHP-1 regulation in myelin reactive T cells- Aim 2: To determine the efficacy of MVP and adoptive T cell therapy in regulating autoimmune disease- PUBLIC HEALTH RELEVANCE: The overall goal of this grant is to define the mechanisms of T cell anergy induced using variants of myelin antigens as a means for controlling autoimmune disease in the central nervous system. T cells play a major role in the pathogenesis of Multiple Sclerosis and the related animal model EAE, indicating that the control of the autoimmune T cell responses is paramount for any beneficial therapy. As a result, all current treatments for MS attempt to target T cells in some fashion. We describe a model for regulation of the T cell response through the activation of the tyrosine phosphatase SHP-1 by MHC variant peptides, suggesting that both could form the basis for future therapies effective against MS as well as other autoimmune diseases. We propose to test our hypothesis using murine EAE models, but our results should be rapidly transferable to human cells. Therefore, our findings are highly relevant to MS and could provide a future treatment by specifically limiting the autoimmune T cell response.